The retinal ATP binding cassette (ABC) transporter, ABCR, is linked to several inherited visual disease syndromes; including Stargardt disease, cone-rod dystrophy, fundus flavimacultitis and age related macular degeneration (ARMD). An overview of genetic analyses clearly demonstrate that missense amino acid substitutions occur with equal frequency in conserved domains, as well as non-conserved domains throughout the whole of the ABCR gene. Our overall aim is to investigate the mechanism of action of ABCR protein and how genetic mutations observed in Stargardt disease and ARMD influence energy transduction in retinal transport so that new and more precise therapies may be developed in the future. [unreadable] [unreadable] (1) We are carrying out a detailed structure-function analysis of nucleotide binding and hydrolysis by ABCR. We plan to test the hypothesis that certain mutations observed in Stargardt disease and ARMD lead to conformational changes which in turn influence nucleotide binding and hydrolysis. This will help us to develop a predictive model for the likely effect of a given mutation on the enzymatic activity and associated structural changes in ABCR. (2) Analyze extracellular domain mutations in substrate (retinal) binding. In this specific aim we address, what are the biochemical consequences of extracellular domain mutations in ABCR function. We will approach this important question from several directions. We will investigate (a) identification of ECD mutations that lead to a loss of retinal stimulation of ATPase; (b) retinal binding by recombinant ECD polypeptides. [unreadable] [unreadable]